Pulmonary arterial hypertension (PAH) is a condition in which the pressure in the lung circulation increases, eventually causing heart failure and death. Although many causes and conditions are found to be associated with PAH, many of them share in common several fundamental pathophysiological features. One important feature among these processes is dysfunction of the endothelium, the internal cellular layer of all vessel walls, which is normally responsible for the production and metabolism of a large array of substances that regulate vessel tone and repair and inhibit clot formation. In the setting of PAH, vascular cell dysfunction can lead to excessive production of deleterious substances and impaired production of protective substances. Whether this is the primary event in the development of PAH or part of a downstream cascade remains unknown, but in either case it is an important factor in the progressive vasoconstriction and vascular proliferation that characterize the disease.
Apelin is highly expressed in the endothelial cells of both systemic and pulmonary vasculature. The apelin receptor (APLNR) is the only known receptor for apelin, and is also highly expressed in the lungs. Apelin knockout mice have been found to be more susceptible to hypoxia induced pulmonary hypertension, and administration of exogenous apelin has shown amelioration of experimental models of pulmonary hypertension. However, exogenous apelin is rapidly cleared from circulation with a plasma half-life of less than 8 mins.
Therefore, a need exists for restoring normal function within these cells to reduce or improve pulmonary arterial hypertension.